The aim of the Core is to perform the electrophysiological analysis on the compounds identified and developed at the other laboratories. This is needed to assess the effectiveness and mechanisms of chemical compounds able to modify the function and processing of the CFTR chloride channel. Small molecules are a promising approach to develop drugs for the treatment of the functional defect in cystic fibrosis. Activators can be used to stimulate channel activity for those CFTR mutants which have a gating defect. Conversely, chemical chaperones or "correctors" could increase the targeting to the plasma membrane of those CFTR mutants which have a trafficking defect (e.g. deltaF508). CFTR inhibitors are also very important as basic research tools for structure-activity correlation and to generate new animal models for cystic fibrosis. The Electrophysiology Core will perform analysis of compounds using transepithelial current measurements and patch-clamp experiments. The former technique, which allows determination of macroscopic CFTR activity, will be useful to perform initial evaluation of compound effectiveness and potency on different CFTR mutants. The latter method will be used for more refined analysis of compound mechanisms. For CFTR activators and inhibitors, the whole-cell, cell attached and excised inside-out configurations of the patch-clamp technique will be useful to determine the effects on channel kinetics, the dependence on CFTR phosphorylation status, sensitivity to membrane potential, and the role of nucleotide binding domains. The results of the Electrophysiology Core will help in the validation and optimization of compounds that could result in development of new drugs for cystic fibrosis treatment.